Clinical and research challenges expected in identifying optimal thromboprophylaxis strategies

With several types of thromboprophylaxis indicated for primary total hip and knee arthroplasty — and only a few agreed-upon guidelines in place — the strategies that orthopaedic surgeons use for preventing venous thromboembolism in their patients vary greatly by geographic region, country, hospital and sometimes within departments. Yet common to them all is the goal of safely and effectively avoiding clinically significant deep vein thrombosis and pulmonary embolism events, while minimizing complications.

“There are several unsolved issues that surgeons are unaware of due to lack of education,” said Ola E. Dahl, MD, DMsci, who has worked to get deep vein thrombosis (DVT) prophylaxis courses on the programs of major orthopaedic meetings worldwide. Progress in the field stands to benefit greatly from increased surgeon education about venous thromboembolism (VTE), Dahl told Orthopaedics Today Europe.

Recently some key advances have also occurred in this area, such as the approval of new oral pharmaceutical options. Other developments underway may foster even better clinical results, such as research into better chemical compounds to fight VTE and new techniques to select the optimal prophylaxis measure for total joint arthroplasty (TJA) patients at greatest risk of a thrombotic event.

“In orthopaedics, the venous thromboembolism issue is not solely [one of] a DVT. It is a thrombin-generation issue,” said Dahl, of Elverum, Norway, past executive director of the International Surgical Thrombosis Forum. “A DVT is simply a local symptom due to some local vascular damage and thrombin generation.”

During thrombin generation, the protein interacts with monocytes, leukocytes and other cells circulating in the body, which then become activated. That process may occur when bone marrow is damaged during total hip arthroplasty (THA) or total knee arthroplasty (TKA), affecting the arterial and venal side of the circulatory system, he said.

Less healthy or older patients, and those with bleeding risks or other comorbidities are typically managed with a customized DVT prophylaxis regimen of medication and other modalities to help prevent DVT, pulmonary embolism (PE), myocardial infarction or stroke, Dahl said.

“The main causes of death after major orthopaedic interventions are vascular deaths due to thromboses and not bleeding,” Dahl stated. “However, the latter is often given more attention by surgeons because it may prolong hospital stay and affects the functional outcome, a topic that involves health politics and medicolegal aspects.”

Ola E. Dahl, MD, DMsci, said surgeons should factor in the drug manufacturers’ interests when assessing the results of any new anticoagulation compounds. Image: Siv Storm Thoresen

Denmark practices

The selection, dosing and duration of prophylactic measures are often left up to the orthopaedic surgeon. However, when guidelines are mandated, as with the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) blood clot prevention guideline published this year, they take precedence.

According to Lars C. Borris, MD, of Aarhus University Hospital in Aarhus, Denmark, Scandinavian orthopaedic surgeons use DVT prophylaxis measures for shorter duration than elsewhere in Europe and the United Kingdom. At his hospital, everyone gets the same prophylaxis protocol — Arixtra (fondaparinux sodium, GlaxoSmithKline).

Compared to using Lovenox (enoxaparin sodium injection, Sanofi-Aventis) for THA and TKA, “We think the documentation for Arixtra is very good, so we have used it for many years,” Borris said.

Borris’ patients typically only get DVT prophylaxis until discharge. “We have no tradition for mechanical measures in Denmark.”

But what has most influenced surgeon preference in his region in favor of 2.5 mg fondaparinux once daily were data finding the injectable drug more effective compared with enoxaparin sodium, even when started postoperatively. Intraoperative bleeding is less concerning, since the drug is not administered until after surgical closure, Borris said.

Aspirin not used

“In our current program, the approach to prophylaxis is sort of orthopaedic surgeon-dependent, although in general we have standard use of anticoagulants,” said Alexander G. Turpie, MD, FRCP, FACC, of Hamilton Health Sciences-General Hospital in Ontario, Canada. The three options orthopaedists there use are low-molecular-weight heparin, fondaparinux sodium and the new oral anticoagulant Xarelto (rivaroxaban, Bayer Healthcare).

Turpie, lead investigator for the RECORD4 clinical trial, noted the same protocols are used for THA and TKA, although duration varies by type of case and other factors. He said because the scientific evidence is insufficient for aspirin as DVT prophylaxis, an approach that some North American surgeons prefer, he does not recommend it.

Gerold Labek, MD, told Orthopaedics Today Europe he modifies the DVT prophylaxis parameters he follows when the patient has a history of previous PE or DVT. “That is the main issue, as well as the general risk factors” of age, size and length of intervention, and tourniquet use.

Otherwise Labek and colleagues at Innsbruck Medical University in Innsbruck, Austria, use rivaroxaban in more than half their TJA cases — the high risk ones — a protocol they started after the European Medicines Agency approved the drug for once daily use in 2008.

Before that they preferred enoxaparin sodium injection. Making the switch involved discussions with the hospital anesthesiology team, with the biggest factor being that rivaroxaban is approved in Europe for peridural and epidural anesthesia, but its competitors are not. The change also required a cost and competitive analysis, Labek noted.

Labek has found non-parenteral approaches to managing VTE easier to administer and simpler for patients to continue 1 or 2 weeks at home, and he is not worried about patient compliance with the oral medications. Also, Labek has noticed no difference in bleeding events with the new drug.

“A DVT or PE is a rare event,” he said. Last year, among nearly 700 THAs and 400 TKAs, there were approximately two clinically-relevant PEs hospital-wide.

The surgeons who spoke with Orthopaedics Today Europe rarely use compression stockings or mechanical prophylactic measures, such as foot pumps. Labek does not use mechanical devices or aspirin, which affects the arterial side; however, all his patients wear compression stockings to pump the venal circuit.

Fast track

According to Borris, a slightly different approach is used for preventing DVT and PE in fast-track TJA situations such as those used in Denmark, where a patient’s pain is well-managed and they are mobilized as soon as possible.

“Our fast-track patients typically go home on postoperative day 3,” and in some centers DVT prophylaxis only continues in those individuals who have risk factors, Borris said.

Labek’s patients are mobilized as early as possible, as are Turpie’s. “But that does not alter their risk for thrombosis to any great extent, so they still need to get anticoagulants,” Turpie said.

When prescribing oral DVT prophylaxis, bleeding complications, hematoma risk, possible liver toxicity, dosing and patient compliance are of concern.

“It is becoming more and more obvious that bleeding is a very important factor and therefore doctors are very keen to avoid bleeding complications,” to the point where some use minimal anticoagulation, Borris said.

Because bleeding problems are also an issue in older patients with age-related reduced kidney function, Borris performs routine kidney tests on all of his patients to determine creatinine clearance and project kidney function.

“The big advantage of these new drugs is that they are given by mouth without a requirement for anticoagulation monitoring.” — Alexander G. Turpie, MD, FRCP, FACC

Starting prophylaxis

Because the highest mortality among patients undergoing TJR occurs on the day of surgery and is driven by thrombin-triggered events, Dahl favors preoperative anticoagulation. “You have to avoid the risk of being too late giving the drug because then the process of thrombin generation has already begun,” he said, noting that a postoperative approach does not target intraoperative cellular clotting aggregation that may cause severe complications.

While preoperative anticoagulation may produce bleeding or a hematoma with TKA, the problem will usually be caught in plenty of time to be treated, Dahl said. “Surgical and wound bleeding is not something patients are dying from.”

At Turpie’s hospital, rivaroxaban is started 6 to 8 hours postoperatively, which has been effective and practical.

“I suspect if you started it — and many surgeons do this — 12 hours after surgery or the next day you won’t lose efficacy and you’ll reduce the bleeding risk.” This mitigates concerns about spinal hematomas developing in spinal anesthesia cases, Turpie said, because the spinal catheter is removed immediately postoperatively.

When to stop

Even more controversial is when to discontinue DVT chemoprophylaxis and whether it should be continued at all upon discharge.

“The big advantage of these new drugs is that they are given by mouth without a requirement for anticoagulation monitoring, which allows us to treat the patients for the recommended 35 to 40 days or 1 month after the procedure,” Turpie said. “Evidence shows that 35 days of treatment is better than 2 weeks of treatment, which is clear for hip replacement patients and suggested in the new American College of Chest Physicians guidelines for TKA patients with previous thrombosis or prolonged surgery.”

Potential test

To detect patients most at risk of dangerous clots, Borris’ colleague, Michael R. Lassen, MD, and researchers developed a test that can be performed with a urine sample to measure thrombin generation.

“If we detect any increased values then we can actively go and do more in these patients. It may find a patient at risk for a PE or DVT complication and give the physician information about what to do next,” Borris said.

Lassen and colleagues expect to publish results with the highly sensitive test. “We think it has a great future because we are really able to monitor [patients] with this,” Borris said.

Going forward

“We have data from epidemiology that obviously has not reached the surgeons and it is important to bring it to them through education. It is important to understand the underlying pathophysiology and the real-life epidemiology in order to apply prophylaxis,” Dahl concluded.

When assessing results of any new anticoagulation compounds, surgeons should factor in the drug manufacturers’ interests and be aware of how hard they push to get more physicians to use their products, he said. They should also understand how to adapt the data from highly sophisticated designed trials on their own non-selected patients.

Dahl urged his orthopaedic colleagues worldwide to remember that DVT prophylaxis for TJR not only affects physicians and health systems, but medical, medicolegal and political issues, as well.

“The surgeon can choose to be better educated and familiar with the pathophysiology, or leave it to another specialty, like the anesthesiologists, or to the regulatory agencies or politicians,” he said. – by Susan M. Rapp

Lars C. Borris, MD, can be reached at the Department of Orthopaedics, Aarhus University Hospital, Nørrebrogade 44, Aarhus C, Denmark; +45-8949-4513; e-mail: larsborr@rm.dk.

Ola E. Dahl, MD, DMsci, can be reached at the Department of Orthopaedics, Elverum Central Hospital, Norway; +47-909-36-946; e-mail: oladahl@start.no. He is also affiliated with the Thrombosis Research Institute, London, United Kingdom and can be reached at +44-792-112-2773.

Gerold Labek, MD, can be reached at Innsbruck Medical University, Anichstrasse 35, Innsbruck A-6020, Austria; +43-512-504-81600; e-mail: gerold.labek@efort.org.

Alexander G. Turpie, MD, FRCP, FACC, can be reached at Hamilton Health Sciences-General Hospital, 237 Barton St., East Hamilton, ON L8L 2X2, Canada; +1-905-528-9946; e-mail: turpiea@mcmaster.ca.

Lars C. Borris, MD, has had various financial, speakers bureau or board member relationships with Bayer HealthCare. Ola E. Dahl, MD, DMsci, has various financial, speakers bureau or board member relationships with AstraZeneca, Bayer HealthCare/Johnson & Johnson, Boehringer Ingelheim, Bristol Meyers Squibb, GlaxoSmithKline, Pharmacia, Pfizer, Sanofi-Aventis and the EMEA. Alexander G. Turpie, MD, FRCP, FACC, has financial relationships with Astellas, Bayer HealthCare, Johnson & Johnson, Portola, Sanofi-Aventis and Takeda.

Is the development of clinical DVT guidelines and their required use in primary THA and TKA warranted?

Cees C.P.M. Verheyen

Conflicting conclusions from identical evidence

There are essential disagreements between 11 major (inter)national guidelines on thromboprophylaxis in orthopaedic surgery. Based on the same available literature, they recommend different regimens. First, there has to be agreement regarding one universal definition for grades of recommendation. Second, no general consensus can be reached as there is no agreement on the relevance of different endpoints.

The dispute on the recommendation whether to use aspirin in total hip arthroplasty (THA) and total knee arthroplasty (TKA) is exemplary for this statement. It depends on the acceptance of the relationship between asymptomatic deep vein thrombosis (DVT), detected by venography or compression ultrasound, and clinically symptomatic venous thromboembolism (VTE). Venographically detected VTE occurs in up to 40% to 60% of THA and TKA patients when no prophylaxis is used. When thromboprophylaxis is administered, 1% to 10% of patients develop symptomatic VTE within 3 months after surgery.

For THA and TKA, respectively, three and two of the 11 guidelines conclude that aspirin is an option, as low-molecular-weight heparin is accepted by all guidelines. It is also important if the emphasis is on efficacy (VTE reduction) or safety (reduce bleeding complications). Different views can be influenced by the mix of hematologists and orthopaedic surgeons on the specific committees. Finally, VTE guidelines should be reviewed and updated on a regular basis because the evidence is evolving rapidly.

If consensus on all these issues could be accomplished, local differences would remain due to differences in health care systems, availability of drugs or devices, and regional variations in risk factors for the development of VTE.

Cees C.P.M. Verheyen, MD, PhD, is from the Department of Orthopaedic Surgery and Traumatologie, Isala Klinieken Zwolle, The Netherlands. He is a board member of the Dutch Orthopaedic Association.

David Warwick

Guidelines are warranted

Thromboembolic events — death and symptomatic VTE — occur after major orthopaedic surgery. It has been repeatedly and scientifically shown that thromboprophylaxis will reduce the risk of symptomatic VTE. One can reasonably extrapolate that the risk of death will also be reduced, although no study is likely to be large enough to prove this.

Many groups have meticulously synthesized the literature. Three of these — the International Consensus Group, the American College of Chest Physicians and the National Institute of Clinical Excellence — are particularly authoritative and have produced comprehensive guidelines. These guidelines are each consistent with each other in advising routine safe and effective prophylaxis whilst allowing leeway for those with exceptional bleeding risks. These guidelines have been criticized for being influenced by an excess of physicians and diluted by a dearth of orthopaedic surgeons; however, these criticisms are dispelled by simply reading the list of contributors. The guidelines all contain enough chemical and mechanical options to account for local or national variations in attitude or availability.

The American Academy of Orthopaedic Surgeons has produced guidelines which curiously regard only PE as the endpoint. They have thus discounted the importance of symptomatic DVT. In doing so, they have used a data set with only a few studies and a rare endpoint, such that no reliable comparisons can be drawn between different potential strategies. This exposes the risk of inadvertently mistaking no evidence of effect for evidence of no effect.

In the absence of guidelines, patients are subject to the risk of being excluded from prophylaxis simply because the prescription was overlooked, or perhaps because of the unintended bias or inevitable gaps in knowledge of their surgeon. Guidelines can ensure that each patient has the opportunity for the best possible care.

David Warwick, MD, FRCS, FRCS(Orth), is a Reader in Orthopaedic Surgery, University of Southampton, United Kingdom.